Pancreas cancer will strike 25,000 families in the United States this year. Families in which there is an aggregation of cancer of the pancreas provide a unique opportunity to identify the molecular genetics of this disease. A genetic understanding of the familial risks can, in turn, form a basis for counseling patients and their families, and for developing new tests to detect this disease earlier. The study of cancer families has led to the discovery of a number of genes for which inherited mutations cause cancer. Examples include: the adenomatous polyposis coli (APC) gene; the von Hippel-Lindau disease tumor suppressor gene; the BRCA1 and BRCA2 genes; the RET proto-oncogene; and the retinoblastoma (RB) gene. Most of the genes identified by studying cancer families have also been found to play a role in the development of sporadic carcinomas. A growing body of literature suggests that there is a familial form of cancer of the pancreas. Studies of these families will have a direct translational impact and we are in a unique position to study these families. The Johns Hopkins Hospital currently treats over 170 patients with pancreas cancer per year, we have established one of the world's largest registries of familial pancreatic cancers, and we have established working collaborations with other cancer family registries. Through our studies of sporadic pancreas cancers we have identified candidate genes and loci for familial cancers, and we have demonstrated, using the same techniques proposed in this application, that germline mutations in p16 are associated with some cases of familial pancreatic carcinoma. We will take advantage of this preliminary work to: 1) determine the patterns of inheritance of pancreatic cancer; 2) determine whether germline mutations in candidate genes lead to the development of pancreatic cancer; and 3) evaluate loci linked to hereditary pancreatic cancer using the method of retained alleles at sites of loss of heterozygosity in primary cancers. These studies should provide a rational basis for predictive gene testing, and for counseling and screening individuals at risk for the development of pancreatic cancer.